Investigating the role of the locus coeruleus‐noradrenergic system during social stress on neuroinflammation and resulting changes in serotonin

Repeated exposure to social stress is known to result in the emergence of depression. While depression is associated with dysregulation of norepinephrine (NE) and serotonin (5‐HT), the mechanism by which this occurs remains unknown. We have previously determined that a history of social stress enhances neuroinflammation in stress sensitive brain regions, proving causal to a depressive‐like phenotype in socially stressed rats. A growing body of evidence suggests that NE is capable of altering proinflammatory cytokine release (ie. IL‐1β) in the brain. Therefore, there were three major goals of this study: 1) to determine if a history of social defeat produced a sensitized neuroinflammatory response to a subsequent stressor within the serotonergic dorsal raphe (DR); 2) because IL‐1β is capable of decreasing 5‐HT synthesis, we sought to determine whether changes in IL‐β in the DR were related to changes in 5‐HT synthesis and 3) rats were treated with DSP‐4 (400μg/rat, icv), a selective retrograde NE neurotoxin that reduces NE levels in LC target regions (ie., DR), to determine the role of NE on stress‐induced IL‐1β levels in the DR and relative 5‐HT expression. Our initial studies identified sensitized stress‐induced proinflammatory cytokine expression in the brains of socially defeated rats compared with rats with a history of control. Furthermore, DSP‐4 significantly increased stress‐induced proinflammatory cytokines in the central amygdala a prominent LC target and induced anhedonia in the 2‐bottle choice sucrose preference test, regardless of stress history. This suggests that LC‐NE has inhibitory control over neuroinflammation in its target regions, including the DR. Since inflammation is known to increase the enzymatic activity of indoleamine‐2,3‐dioxygenase (IDO), resulting in a shift from 5‐HT synthesis to the production of kynurenine (Kyn), stress‐induced inflammation in the DR is likely associated with a concomitant increase in IDO activity and a reduction of 5‐HT. Together these data suggest that LC‐NE activity may suppress neuroinflammatory drive under conditions of stress and that impaired LC‐NE firing may serve as a mechanistic link between stress‐induced neuroinflammation, dysfunction in the 5‐HT system, and expression of depressive‐like behaviors. These studies seek to identify mechanisms involved in stress susceptibility, in order to reveal novel targets useful in the treatment of stress‐related psychosocial disorders. Support or Funding Information 15SDG22430017 and P20GM103641